Lai-Xi Zhao,1, En-Tang Wang,2, Wen-Hao Jia,1 Mo-Han Wang,5 Zhao Pan,4 Liang Dong,4 Hui-Qin Wen,3 Wen-Hua Xu,1 Rui Xu1 1College 2Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, People’s Republic of China; 3Department of Blood Transfusion, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China; 4Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, People’s Republic of China; 5Department of Oral and Maxillofacial Surgery, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People’s Republic of ChinaThese authors contributed equally to this workCorrespondence: Rui Xu, Email dentistxr@126.com Wen-Hua Xu, Email xuwenhua@ahmu.edu.cnAbstract: Early oral squamous cell carcinoma (OSCC) is frequently missed because conventional imaging and biopsy are poorly suited to detect subtle, preclinical molecular changes. Emerging salivary exosome nanodiagnostics aims to convert an anatomically proximal, information-rich nanoscale biospecimen into quantitative and repeatable readouts for screening and longitudinal monitoring. Clinical translation, however, is constrained by four bottlenecks: (i) pre-analytical variability in saliva collection, processing, and storage; (ii) yield–purity trade-offs during vesicle enrichment; (iii) low-abundance tumor-derived signals masked by abundant background vesicles; and (iv) biomarker heterogeneity that limits robustness across cohorts. Here, we integrate the landscape of salivary exosomal biomarkers (nucleic acids, proteins, and other cargo) and synthesize nanotechnology-enabled solutions that directly address these barriers, including microfluidic and affinity-based enrichment, nucleic-acid amplification circuits (eg, RCA, HCR, CHA) for signal gain, and optical/electrochemical transduction (eg, SPR, SERS) compatible with microliter-scale samples. Beyond listing platforms, we propose a unifying framework: co-design capture and readout to preserve biological specificity, match biomarker modality to detection physics, and prioritize multi-marker panels with transparent analytical benchmarks. Finally, we outline a translational roadmap spanning standardization, reproducibility, prospective multicenter validation, manufacturability, and regulatory readiness to accelerate clinically actionable early OSCC detection. Keywords: oral squamous cell carcinoma, salivary exosomes, exosomal biomarkers, liquid biopsy, nanodiagnostics, nanoplatform
LX et al. (Thu,) studied this question.